PROJECT SUMMARY Peripartum depression and anxiety are very common, but poorly understood, disorders that negatively affect a tremendous number of women and their infants. Indeed, more than 15% of the 4 million pregnant and recently parturient women in the U.S. each year suffer from depression and at least 10% suffer from anxiety. Selective serotonin reuptake inhibitors (SSRIs) are the most-often prescribed medications for peripartum depression or anxiety. This is despite a lack of knowledge about SSRI's neurochemical effects, or strong evidence for their clinical efficacy as currently prescribed, specifically during this unique period of reproduction. It is unknown if SSRIs affect the pregnant and postpartum brain differently than the non-maternal brain. Reproduction involves some of the most dramatic neurobiological modifications in adulthood. These include the central serotonin (5-HT) systems SSRIs act upon. However, there are no thorough studies of how central 5-HT changes across female reproduction. It is also mostly unknown how prepartum stress, which predisposes women for psychopathology, affects the normative changes in central 5-HT. Thus, it is impossible to determine how, when, and where SSRIs have their greatest capacity to alleviate maternal depression and anxiety. The long-term goal of my research is to better understand how pregnancy and motherhod modify central 5- HT and the downstream consequences for female brain structure and function, which is critical for understanding maternal psychopathology. The objective of this R03 project is to test in detail the hypothesis that reproduction generates a host of changes in the 5-HT system at its source in the midbrain raphe, and in forebrain sites involved in maternal depression and anxiety in a laboratory rat model. I also hypothesize that reproduction affects brain derived neurotrophic factor (BDNF) and its TrkB receptor, which partly mediate SSRIs' neuroplastic and anti-depressive effects. I further hypothesize that pregnancy stress derails these normative brain changes, and that fluoxetine will prevent that derailment. The work proposed will use a variety of research tools (PCR, Western blotting, IHC, HPLC) and is innovative as the first to concurrently measure levels of the 5-HT synthesizing enzyme TPH2, 5-HT and its major metabolite, 5-HT 1A/2A/2C receptors, the 5- HT transporter, BDNF, and TrkB in the female brain through pregnancy and lactation. It is also innovative in that unstressed females will be compared to stressed females, as well as to non-reproducing female rats. This important basic research will contribute to understanding the changes in the central 5-HT and BDNF systems across female reproduction and how they are affected by prepartum stress. More broadly, the results will enhance knowledge about neurochemistry of the maternal brain, and the potential effects of SSRIs during pregnancy and postpartum. This knowledge is highly significant because it has the potential to improve the treatment of millions of women and their infants negatively affected by postpartum depression and anxiety.